DUTPase inhibitors

Abstract

Deoxyuridine derivatives of the formula (I) where R 1 is H or various substituents; D is —NHCO—, —CONH—, -0-, —C(═O)—, —CH═CH, —C≡C—, —NR 5 —; R 4 is hydrogen or various substituents; R 5 is H, C 1 -C 4 alkyl, C 1 -C 4 alkanoyl; E is Si or C; R 6 , R 7 and R 8 are independently selected from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl or a stable monocyclic, bicyclic or tricyclic ring system; G is —O—, —S—, —CHR 10 —, —C(═O)—; J is —CH 2 —, or when G is CHR 10 may also be —O— or —NH—; R 10 is H, F, —CH 3 , —CH 2 NH 2 , —CH 2 OH; —OHR 11 is H, F, —CH 3 , —CH 2 NH 2 , —CH 2 OH, —CH(OH)CH 3 , CH(NH 3 )CH 3 ; or R 10 and R 11 together define an olefinic bond, or together form a —CH 2 -group, thereby defining a cis or trans cyclopropyl group; have utility in the prophylaxis or treatment of protozoal diseases such as malaria.

1. A method for the treatment of parasitic infections that cause malaria in man or a zoonose vector comprising the administration of an effective amount of a compound of formula I to a patient in need thereof, or to the vector: 
       
         
           
           
               
               
           
         
         where 
         R 1  is H, C 1 -C 5  alkyl, C 2 -C 5  alkenyl, C 2 -C 5  alkynyl or a 5 or 6 membered, saturated or unsaturated ring containing 0 to 3 heteroatoms selected from N O and S, the alkyl, alkenyl, alkynyl or ring being independently optionally substituted with R 4 ; 
         D is —NHCO—, —CONH—, —O—, —C(═O)—, —CH═CH, —C≡C—, —NR 5 —; 
         R 4  is hydrogen, halo, cyano, amino, nitro, carboxy, carbamoyl, hydroxy, oxo, C 1 -C 5  alkyl, C 1 -C 5  haloalkyl, C 1 -C 5  alkyloxy, C 1 -C 5  alkanoyl, C 1 -C 5  alkanoyloxy, C 1 -C 5  alkylthio, —N(C 0 -C 3 -alkyl) 2 , hydroxymethyl, aminomethyl, carboxymethyl; —SO 2 N(C 0 -C 3 -alkyl), —SO 2 C 1 -C 5 -alkyl; 
         R 5  is H, C 1 -C 4  alkyl, C 1 -C 4  alkanoyl; 
         E is Si or C; 
         R 6 , R 7  and R 8  are independently selected from C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl or a stable monocyclic, bicyclic or tricyclic ring system which is saturated or unsaturated in which each ring has 0 to 3 heteroatoms selected from N, O and S, 
         R 6 , R 7  and R 8  are independently optionally substituted with R 4 ; 
         G is —O—, —S—, —CHR 10 —, —C(═O)—; 
         J is —CH 2 —, or when G is CHR 10  may also be —O— or —NH—; 
         R 10  is H, F, —CH 3 , —CH 2 NH 2 , —CH 2 OH, —OH; or a pharmaceutically acceptable ether, ester or amide created through reaction of the preceding hydroxyl and/or amino group; 
         R 11  is H, F, —CH 3 , —CH 2 NH 2 , —CH 2 OH, CH(OH)CH 3 , CH(NH 2 )CH 3 ; or a pharmaceutically acceptable ether, ester or amide created through reaction of the preceding hydroxyl and/or amino group; or 
         R 10  and R 11  together define an olefinic bond, or together form a —CH 2 -group, thereby defining a cis or trans cyclopropyl group; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
       2. The method according to  claim 1 , wherein G is —O— or —CH 2 —. 
     
     
       3. The method according to  claim 1  wherein R 10  and R 11  define an olefinic bond or a cyclopropyl group. 
     
     
       4. The method according to  claim 1 , wherein R 11  is H; CH 2 OH or a pharmaceutically acceptable ether or ester thereof; or CH 2 NH 2  or a pharmaceutically acceptable amide thereof. 
     
     
       5. The method according to  claim 1 , wherein R 1  is H. 
     
     
       6. The method according to  claim 1 , wherein D is —O— or —NH—. 
     
     
       7. The method according to  claim 6 , wherein C 0- C 3 -alkylene-D-C 0 -C 3 -alkylene is oxymethylene, oxyethylene or oxypropylene. 
     
     
       8. The method according to  claim 6 , wherein C 0- C 3 -alkylene-D-C 0 -C 3 -alkylene is aminomethylene, aminoethylene or aminopropylene. 
     
     
       9. The method according to  claim 1 , wherein at least two of R 6 , R 7  and R 8  are aryl. 
     
     
       10. The method according to  claim 1 , wherein R 6  is optionally substituted phenyl. 
     
     
       11. The method according to  claim 10  wherein R 8  is optionally substituted phenyl or pyridyl. 
     
     
       12. The method according to  claim 1  wherein E is C. 
     
     
       13. The method according to any preceding claim, wherein the zoonose vector is a parasite and a  Plasmodium  species.